ATMCHK2p53

ATMCHK2p53 denotes the cooperative signaling module comprising the ATM kinase, the CHK2 checkpoint kinase, and the tumor suppressor p53, which together mediate cellular responses to DNA double-strand breaks. While not a single protein, the axis reflects a conserved pathway that links damage detection to cell cycle control and apoptosis.

Activation begins with ATM sensing double-strand breaks and undergoing autophosphorylation, forming active dimers. ATM phosphorylates multiple substrates, including CHK2 on Thr68 and p53 on Ser15. Phosphorylation of CHK2 promotes further activation, enabling it to relay signals to p53 and other effectors.

CHK2 directly phosphorylates p53 on Ser20, reducing interaction with MDM2 and stabilizing p53. Stabilized p53 accumulates in the nucleus and drives transcription of target genes, notably CDKN1A (p21), GADD45, and pro-apoptotic members such as BAX and PUMA, shifting the outcome toward cell cycle arrest or apoptosis depending on damage extent.

p21 enforces G1/S arrest by inhibiting cyclin-dependent kinases, allowing DNA repair. If damage is irreparable, p53 triggers apoptosis to prevent propagation of damaged cells. The axis is integrated with MDM2, a p53 target that mediates ubiquitination and degradation of p53, forming a negative feedback loop.

Clinical relevance includes inherited defects in ATM, CHEK2, or TP53 increasing cancer risk (e.g., ataxia-telengiectasia, Li-Fraumeni syndrome, familial breast cancer). In cancer therapy, inhibitors of ATM or CHK2 are explored to enhance tumor radiosensitivity; p53 status influences treatment outcomes.